Calorie restriction

Calorie restriction, or caloric restriction, or energy restriction, is a dietary regimen that reduces calorie intake without incurring malnutrition or a reduction in essential nutrients. "Reduce" can be defined relative to the subject's previous intake before intentionally restricting calories, or relative to an average person of similar body type. Commonly consumed food components containing calories are carbohydrates, proteins and fat.

In preliminary research, some non-human species on calorie restriction diets without malnutrition may exhibit slowing of the biological aging process, resulting in an increase in both median and maximum lifespan,[1][2] but this effect is not universal.[3] In humans, the long-term health effects of moderate caloric restriction with sufficient nutrients are unknown.[4]

The term "calorie restriction" as used in gerontology refers to dietary regimens that reduce calorie intake without incurring malnutrition.[4] If a restricted diet is not designed to include essential nutrients, malnutrition may result in serious deleterious effects, as shown in the Minnesota Starvation Experiment.[5] This study was conducted during World War II on a group of lean men, who restricted their calorie intake by 45%[6] for 6 months and composed roughly 77%[7] of their diet with carbohydrates.[5] As expected, this malnutrition resulted in many positive metabolic adaptations (e.g. decreased body fat, blood pressure, improved lipid profile, low serum T3 concentration, and decreased resting heart rate and whole-body resting energy expenditure), but also caused a wide range of negative effects, such as anemia, edema, muscle wasting, weakness, neurological deficits, dizziness, irritability, lethargy, and depression.[8]

Short-term studies in humans report a loss of muscle mass and strength and reduced bone mineral density.[9] However, whether or not the reduction in bone mineral density actually harms bone health is unclear.[10] In a study in premenopausal women, bone mineral density after weight loss was higher when normalized for body weight;[10] reduced bone mineral density is also observed in humans undergoing long-term calorie restriction with adequate nutrition, but no fractures have been reported[11] and the reduction in bone mineral density was not associated with deleterious changes in bone microarchitecture.[10]

The authors of a 2007 review of the caloric restriction literature warned that "[i]t is possible that even moderate calorie restriction may be harmful in specific patient populations, such as lean persons who have minimal amounts of body fat."[12]

Caloric restriction diets typically lead to reduced body weight, yet reduced weight can come from other causes and is not in itself necessarily healthy. In some studies, low body weight has been associated with increased mortality, particularly in late middle-aged or elderly subjects. Low body weight in the elderly can be caused by pathological conditions associated with aging and predisposing to higher mortality (such as cancer, chronic obstructive pulmonary disorder, or depression) or of the cachexia (wasting syndrome) and sarcopenia (loss of muscle mass, structure, and function).[13] One study linked a body mass index lower than 18 in women with increased mortality from noncancer, non−cardiovascular disease causes.[14] The authors attempted to adjust for confounding factors (cigarette smoking, failure to exclude pre-existing disease); others argued that the adjustments were inadequate.[15]

Such epidemiological studies of body weight are not about caloric restriction as used in anti-aging studies; they are not about caloric intake to begin with, as body weight is influenced by many factors other than energy intake, Moreover, "the quality of the diets consumed by the low-body mass index individuals are difficult to assess, and may lack nutrients important to longevity."[4] Typical low-calorie diets rarely provide the high nutrient intakes that are a necessary feature of an anti-aging calorie restriction diet.[17][18][19] As well, "The lower-weight individuals in the studies are not a caloric restriction because their caloric intake reflects their individual ad libitum set-points and not a reduction from that set-point."[4]

Long-term caloric restriction at a level sufficient for slowing the aging process is generally not recommended in children, adolescents, and young adults (under the age of approximately 21), because this type of diet may interfere with natural physical growth, as has been observed in laboratory animals. In addition, mental development and physical changes to the brain take place in late adolescence and early adulthood that could be negatively affected by severe caloric restriction.[21]Pregnant women and women trying to become pregnant are advised not to practice calorie restriction, because low BMI may result in ovulatory dysfunction (infertility), and underweight mothers are more prone to preterm delivery.[21]

Even though there has been research on caloric restriction for over 70 years, the mechanism by which caloric restriction works is not well understood.[2] Some explanations include reduced core body temperature,[23] reduced cellular divisions, lower metabolic rates and hormesis, according to one review of laboratory research.[24]

Caloric restriction lowers the core body temperature, a phenomenon believed to be an adaptive response to reduce energy expenditure when nutrients availability is limited. Lowering the temperature may prolong the lifespan of cold blooded animals. Mice, which are warm blooded, have been engineered to have a reduced core body temperature which increased the lifespan independently of calorie restriction.[23]

Some research has pointed toward hormesis as an explanation for the benefits of caloric restriction, representing beneficial actions linked to a low-intensity biological stressor such as reduced calorie intake.[24] As a potential role for caloric restriction, the diet imposes a low-intensity biological stress on the organism, eliciting a defensive response that may help protect it against the disorders of aging.[25] In other words, caloric restriction places the organism in a defensive state so that it can survive adversity, resulting in improved health and longer life.[24] This switch to a defensive state may be controlled by longevity genes (see below).[26]

It has been recently argued that during years of famine, it may be evolutionarily desirable for an organism to avoid reproduction and to up-regulate protective and repair enzyme mechanisms to ensure that it is fit for reproduction in future years. This argument seems to be supported by recent work studying hormones. Prolonged severe CR lowers total serum and free testosterone while increasing sex hormone binding globulin concentrations in humans; these effects are independent of adiposity.[27]

Lowering of the concentration of insulin and substances related to insulin, such as insulin-like growth factor 1 and growth hormone, has been shown to up-regulate autophagy, the repair mechanism of the cell.[28] A related hypothesis suggests that caloric restriction works by decreasing insulin levels and thereby up-regulating autophagy,[28][29] but caloric restriction affects many other health indicators, and it is still undecided whether insulin is the main concern.[30] Calorie restriction has been shown to increase DHEA in primates, but it has not been shown to increase DHEA in post-pubescent primates.[31][32] The extent to which these findings apply to humans is still under investigation.

Evidence suggests that the biological effects of caloric restriction are closely related to chromatin function.[33]
One study determined that the gene PHA-4 is responsible for the longevity behind calorie restriction in roundworms, "with similar results expected in humans".[34]

Preliminary research indicates that sirtuins are activated by fasting and serve as "energy sensors" during metabolism.[35] Sirtuins, specifically Sir2 (found in yeast) have been implicated in the aging of yeast,[36] and are a class of highly conserved, NAD+-dependent histone deacetylaseenzymes.[37] Sir2 homologs have been identified in a wide range of organisms from bacteria to humans.[36][38] Yeast has 3 SIR genes (SIR2, SIR3, and SIR4) that are responsible for silencing mating type loci, telomeres, and rDNA.[39] Although all three genes are required for the silencing of mating type loci and telomeres, only SIR2 has been implicated in the silencing of rDNA.[40] In addition, SIR2 related genes also regulate formation of some specialized survival forms, such as spores in yeast[41] and daher larvae in C. elegans.[42] A study done by Kaeberlein et al. (1999) in yeast found that deletions of Sir2 decreased lifespan, and additional copies increased lifespan.[38]

In many calorie restriction studies, it is believed that Sir2 mediates the longevity effects from calorie restriction for several reasons. First, it was found that in yeast without SIR2, calorie restriction did not impart longevity in yeast;[43] second, in Sir2 mutants an abundance of extra-chromosomal ribosomal DNA circles (that typically limit lifespan) has been observed, and that mitigation of these circles restore regular life span, but still are resistant to calorie restriction-mediated longevity;[44][45] third, that caloric restriction increases the activity of Sir2 in vivo.[46] Although Sir2 has been implicated in calorie restriction-mediated longevity, the method by which Sir2 is regulated under caloric restriction is still debated.

Work on the mechanisms of caloric restriction has given hope to the synthesizing of future drugs to increase the human lifespan by simulating the effects of calorie restriction. In particular, the large number of genes and pathways reported to regulate the actions of caloric restriction in model organisms represent attractive targets for developing drugs that mimic the benefits of CR without its side effects.[47][48][49]

Sir2, or "silent information regulator 2", is a sirtuin, discovered in baker's yeast cells, that is hypothesized to suppress DNA instability.[50] In mammals, Sir2 is known as SIRT1. One proponent of the view that the gene Sir2 may underlie the effect of calorie restriction in mammals by protecting cells from dying under stress.[51] It is suggested that a low-calorie diet that requires less Nicotinamide adenine dinucleotide to metabolize may allow SIRT1 to be more active in its life-extending processes, possibly by a mechanism of SIRT1 releasing fat from storage cells.[52]

Attempts are being made to develop drugs that act as CR mimetics, and much of that work has focused on a class of proteins called sirtuins.[53]Resveratrol has been reported to activate SIRT1 and extend the lifespan of yeast,[54] nematode worms, fruit flies,[55] vertebrate fish,[56] and mice consuming a high-caloric diet.[57] However, resveratrol does not extend life span in normal mice[58] and the effect of resveratrol on lifespan in nematodes and fruit flies has been disputed.[59]

There are studies that indicate that resveratrol may not function through SIRT1[60][61] but may work through other targets.[62][63] A clinical trial of the resveratrol formulation SRT501 was suspended.[64]

Ancient medicine, the province of Hippocrates and Galen after him, taught that the very fat were destined to die suddenly more often than the slender.[65] Around 1000 A.D. Avicenna taught the elderly to eat less than when they were young.[65] Around 1500 because his health was failing due to gluttony, the Venetian nobleman Luigi Cornaro adopted a calorie restricted diet at age 35 and went on to live to be 102 years old. His very successful book Discorsi della vita sobria[66] described his regimen, restricting himself to 350 g (12 oz) of food daily (including bread, egg yolk, meat, and soup) and 410 ml (14 US fl oz) of wine.[67][65]

In 1919 after observing starvation in Central Europe during World War I, Francis Benedict and his colleagues published Human Vitality and Efficiency Under Prolonged Restricted Diet[68] based on their experiment with 10% calorie reduction on male college students at the Carnegie Institution for Science.[69] Reduced rations had turned out to be "not necessarily cataclysmic." Faced with some evidence for what was unknown at the time but today is called metabolic adaptation, Benedict wanted to find the science behind what appeared to be an adjustment in metabolic rate when food intake was below energy expenditure.[69]

Hoping to learn how to refeed the people who had starved during World War II, between 1944 and 1945, 36 healthy conscientious objectors participated in the Minnesota Starvation Experiment, published in 1950 as The Biology of Human Starvation by lead investigator Ancel Keys and colleagues.[70][8] Because the men were receiving 40% CR and subject to malnutrition this study was not one of calorie restriction per se.[nb 1]

EA Vallejo published a study of approximately 35% CR in the Spanish language in 1957, testing CR without malnutrition in nonobese elderly persons.[72][73] About 30% CR for six months was achieved accidentally in the Biosphere 2 experiment during the 1990s.[72]

Studies have been conducted to examine the effects of calorie restriction with adequate intake of nutrients in humans; however, long-term effects are unknown.[4] One objection to calorie restriction in humans is a claim that the physiological mechanisms determining longevity are complex, and that the effect would be small to negligible.[74] Effects of calorie restriction in humans over multiple years or decades may be small in comparison to conventional medical and public health interventions, but have not yet been clearly determined.[4][75]

A review of the effects of calorie restriction on the aging heart and vasculature concluded that "Data from animal and human studies indicate that [beyond the effects of "implementation of healthier diets and regular exercise"], more drastic interventions, i.e., calorie restriction with adequate nutrition (CRAN), may have additional beneficial effects on several metabolic and molecular factors that are modulating cardiovascular aging itself (e.g., cardiac and arterial stiffness and heart rate variability)."[76] Studies of long-term practitioners of rigorous calorie restriction show that their risk factors for atherosclerosis are substantially improved in a manner consistent with experimental studies in rodent models of atherosclerosis and nonhuman primates.[76] Risk factors such as c-reactive protein; serum triglycerides, low-density lipoprotein, high-density lipoprotein; blood pressure; and fasting blood sugar, are substantially more favorable than persons consuming usual Western diets and comparable or better than long-term endurance exercisers.[76] Similar effects were also seen during a "natural experiment" in Biosphere 2,[76] and effects on blood pressure, cholesterol level, and resting heart rate were seen in subjects in the “Minnesota Starvation Experiment” during World War II.[8] Cardiac "diastolic function was better in subjects who practiced strict calorie restriction for 3–15 years than that in healthy age- and sex-matched control subjects ... calorie restriction subjects had less ventricular stiffness and less viscous loss of diastolic recoil, both of which would be consistent with less myocardial fibrosis.[76] "These effects, in combination with other benefits of calorie restriction, such as protection against obesity, diabetes, hypertension, and cancer, suggest that CR may have a major beneficial effect on health span, life span, and quality of life in humans."[76]

In a 2017 collaborative report on rhesus monkeys by scientists of the US National Institute on Aging and the University of Wisconsin, caloric restriction in the presence of adequate nutrition was effective in delaying the effects of aging.[31][77] Older age of onset, female sex, lower body weight and fat mass, reduced food intake, diet quality, and lower fastingblood glucose levels were factors associated with fewer disorders of aging and with improved survival rates.[31][77] Specifically, reduced food intake was beneficial in adult and older primates, but not in younger monkeys.[31] The study indicated that caloric restriction provided health benefits with fewer age-related disorders in elderly monkeys and, because rhesus monkeys are genetically similar to humans, the benefits and mechanisms of caloric restriction may apply to human health during aging.[31]

It has been known since the 1930s that reducing the number of calories fed to laboratory rodents increases their life spans. The life extension varies for each species, but on average there was a 30–40% increase in life span in both mice and rats.[30] In late adulthood, acute CR partially or completely reverses age-related alterations of liver, brain and heart proteins, and mice placed on CR at 19 months of age show an increases in life span.[78]

Fungi models are very easy to manipulate, and many crucial steps toward the understanding of aging have been made with them. Many studies were undertaken on budding yeast and fission yeast to analyze the cellular mechanisms behind increased longevity due to calorie restriction. First, calorie restriction is often called dietary restriction because the same effects on life span can be achieved by only changing the nutrient quality without changing the number of calories. Data from Guarente and others showed that genetic manipulations in nutrient-signaling pathways could mimic the effects of dietary restriction. In some cases, dietary restriction requires mitochondrial respiration to increase longevity (chronological aging), and in some other cases not (replicative aging). Nutrient sensing in yeast controls stress defense, mitochondrial functions, Sir2, and others. These functions are all known to regulate aging. Genes involved in these mechanisms are TOR, PKA, SCH9, MSN2/4, RIM15, and SIR2.[79][80][81][82][83] Importantly, yeast responses to CR can be modulated by genetic background. Therefore, while some strains respond to calorie restriction with increased lifespan, in others calorie restriction shortens it [84]

Calorie restriction preserves muscle tissue in nonhuman primates[85][86] and rodents.[87][88] Mechanisms include reduced muscle cell apoptosis and inflammation;[87] protection against[88] or adaptation to[85] age-related mitochondrial abnormalities; and preserved muscle stem cell function.[89] Muscle tissue grows when stimulated, so it has been suggested that the calorie-restricted test animals exercised more than their companions on higher calories, perhaps because animals enter a foraging state during calorie restriction. However, studies show that overall activity levels are no higher in calorie restriction than ad libitum animals in youth.[90] Laboratory rodents placed on a calorie restriction diet tend to exhibit increased activity levels (particularly when provided with exercise equipment) at feeding time. Monkeys undergoing calorie restriction also appear more restless immediately before and after meals.[91]

Observations in some accounts of animals undergoing calorie restriction have noted an increase in stereotyped behaviors.[91] For example, monkeys on calorie restriction have demonstrated an increase in licking, sucking, and rocking behavior.[92] A calorie restriction regimen may also lead to increased aggressive behavior in animals.[91]

It has sometimes been suggested that the lives of calorie-restricted animals are only extended relative to control animals whose lives are artificially shortened by weight-gain from unnatural ad libitum feeding in the laboratory.[93] However, studies designed to test this hypothesis suggest that reduced fat mass is not a major contributor to the longevity effects of calorie restriction.[4]

^Binge-Eating Disorder: Clinical Foundations and Treatment (1 ed.). The Guilford Press. 2007. p. 15. ISBN978-1-59385-594-9. It can be concluded that caloric restriction does not appear to be associated with the development of binge eating in individuals who have never reported problems with binge eating.